Natural products have been the most significant source of drugs and drug leads in history. Many conventional therapies have been developed from nature-derived materials. Their dominant role in cancer chemotherapeutics is clear, with about 74% of anticancer compounds being either natural products or natural product-derived. It is estimated that approximately 25% of the drugs prescribed worldwide, at present, come from plants and 60% of anti-tumor/anti-infectious drugs, already on the market or under clinical investigations, are of natural origin (Wang et al., 2007).
Higher Basidiomycetes mushrooms (HBM) represent a major and still largely unexploited source of new pharmaceutical products. Of approximately 15,000 known species, 2,000 are safe for human consumption, and about 650 of them possess medicinal properties. Of about 650 mushroom species with known medicinal properties, only about 20 species are in use at the present. Most traditional knowledge about medicinal properties of HBM arrives from the Far East (China, Japan, Korea, and Russian Siberia). Many pharmaceutical substances with potent and unique properties have recently been extracted from mushrooms. Unique anticancer remedies were prepared from these extracts such as polysaccharides lentinan, krestin, and schizophyllan (Mizuno, 1999).
Present studies suggest that extracts and active agents obtained from HBM act as immunomodulators or as biological response modifiers (BRM). They help the body to strengthen itself and fight off illness by maintaining physiological homeostasis and restoring the body's Host Defense Potentiators (HDP), which can have immune system enhancement properties. This benefit is one of the reasons why they are currently used as adjuncts to cancer treatment in many countries. In Japan, Russia, China, and the USA several polysaccharide anticancer and immunomodulating agents have been developed from the fruiting body, mycelia, and culture medium of various medicinal mushrooms (Lentinus edodes, Ganoderma lucidum, Schizophyllum commune, Trametes vesicolor, Inonotus obliquus, Hypsizigus marmoreus, and Flammulina velutipes) (Ikekawa, 2001).
Many edible mushrooms were used in traditional folk medicine including Lentinus edodes (shiitake mushroom). Grifola frondosa (maitake), Hericium erinaceus, Flammulina velutipes, Pleurotus ostreatus, and Tremella mesenterica which are also sources of relatively pure bioactive compounds for medical usage, while other non-edible species, such as Ganoderma lucidum, Schizophyllum commune, and Trametes versicolor, are used only for their medicinal properties.
Fungal metabolites have been gaining scientific interest as they were found to possess medicinal properties. Many studies on medicinal mushrooms proved their potential not only as dietary supplements and immunoenhancers (Wasser & Weis, 1999a, b) but also as modulators of various cellular responses (Zaidman et al., 2005).
The diversification of medicinal higher fungi represents great potential for new drugs. As known, cancer chemotherapy has relied mostly on cytotoxic drugs, which inhibit tumor cell proliferation and cause cell death. Cytotoxic activities against various tumor cell lines of higher fungi secondary metabolites were widely investigated in the past decades.
Low-molecular-weight (LMW) substances with fungal origin can penetrate the cell membrane and interfere, in particular, with cellular pathways linked to processes such as inflammation, carcinogenesis, cell differentiation and survival, metastasis, etc. On the basis of these facts, medicinal mushrooms were established as a novel and promising source for natural therapeutics that can be successfully applied in the treatment of different diseases, including cancer (Smith et al., 2002). Extracts from many mushrooms, as well as specific active substances isolated from such extracts (e.g. Yassin et al., 2003), have been shown to exhibit anti-cancer activity.
For example, Muller et al. (2006) found that methanol:water extracts from fruiting bodies of G. lucidum induce apoptosis for each of the 26 panel of human cancer cell lines examined, in a dose-dependent manner.
Wu et al. (2006) used ethyl acetate extracts from the mycelium of Cordyceps sinensis to show the inhibitory effect on various cancer cell lines. They projected the inhibitory effect to ergosterol and related compounds present in the extract.
Lu et al. (2004) used ethanol:water extracts of the Coriolus vesicolor fruiting bodies to inhibit the proliferation of Burkitt's lymphoma B-cell line (HL-60) and human acute promyelocytic leukemia cell lines (NB-4), in a dose-dependent manner, with more than 90% suppression, and no significant suppression on the proliferation of normal liver cell lines (WRL).
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid malignancies. It is the thirteenth most common cancer worldwide and one of the leading causes of cancer death with 232,000 new cases each year and 213,000 deaths. In the United States and Israel, pancreatic cancer is the fourth leading cause of cancer related mortalities. In the year 2010 an estimated 43,140 patients were diagnosed with pancreatic cancer; 36,800 patients died of their disease in the US alone.
PDAC is a disease with very poor prognosis mainly because of insensitivity to most standard therapies including chemotherapy, radiotherapy, and immunotherapy. Therefore, surgical resection offers, at the moment, the only potential prospect for a cure.
For all stages combined, the 1- and 5-year relative survival rates of PDAC are 24% and 5%, respectively. Even for those people diagnosed with local disease, the 5-year survival is merely 20%. These unfortunate statistics reflect the advanced stage at which most patients with pancreatic cancer are diagnosed and the paucity of effective chemotherapeutic regimens for advanced disease.
To our knowledge, no previous publication disclosing the activity of Cyathus striatus mushroom extracts on pancreatic cancer cells exists. We have found some data on other members of the genus Cyathus, e.g., Cyathus bulleri (Kang et al., 2007), Cyathus stercoreus, Cyathus olla, Cyathus africanus, Cyathus colensoi, Cyathus gansuensis, Cyathus sp.39, Cyathus pallidus, Cyathus intermedius, Cyathus sp.34, Cyathus sp. 37, Cyathus nigroalbus, Cyathus sp. 73, and Cyathus luxiensis (Liu & Zhang, 2004). Most of the data pertains to antimicrobial or antifungal properties. The mushroom Cyathus striatus was investigated in our lab for the first time for its anticancer properties. In an extensive screening of 242 crude mushroom extracts, Petrova et al. (2007) from our lab demonstrated a potent growth-inhibitory effect of some of the extracts, e.g. from C. striatus, on MCF7-human breast cancer cell line, PC3 and DU145-human androgen-independent prostate cancer, 9L-rat glioblastoma, and Baf3/p185 Bcr-Abl-B-lymphocytes, a laboratory model of CML. Petrova also found C. striatus to modulate IκBα levels even in the lowest concentration used (5 and 1 μg/ml) and demonstrated the ability to inhibit both IκBα phosphorylation and degradation (Petrova et al., 2007).